Patent GB-1416695-A (GB)
Title: Substituted benzofurans
IPC: C07D307/79
Filed: 1972-11-15
Abstract: 1416695 3 - Phenylbenzofuranalkanoic acids and their derivatives RIKER LABORATORIES Inc 15 Nov 1972 [16 Nov 1971] 52811/72 Heading C2C The invention comprises compounds of formula and their pharmaceutically acceptable salts (when Z is OH), wherein Z is OH, C 1-4  alkoxy, NH 2 , NHY<SP>1</SP>, NY<SP>1</SP>Y<SP>2</SP>, O(CH 2 ) m NY<SP>1</SP>Y<SP>2</SP>, OCH 2 OMe, OCH 2 OCOY 1 , NHOH or NHNH 2 ; R<SP>1</SP> is H, Me or Et; R<SP>2</SP> is H or R<SP>1</SP>R<SP>2</SP> is CH 2 =; R<SP>3</SP>, R<SP>4</SP> are each H or R<SP>3</SP>-R<SP>4</SP> is a direct bond; R<SP>5</SP> is H or C 1-4  alkyl, or (when R<SP>3</SP>-R<SP>4</SP> is a direct bond) halogen; Y<SP>1</SP>, Y<SP>2</SP> are each C 1-4  alkyl, or NY<SP>1</SP>Y<SP>2</SP> is pyrrolidino, piperidino, morpholino or 4-methylpiperazino; Y<SP>3</SP> is C 1-4  alkyl or alkoxy, halogen, NO 2 , OH or di-(C 1-4  alkyl) amino; Y<SP>4</SP> is C 1-4  alkyl, haloalkyl, alkoxy, haloalkoxy, alkylthio, alkylsulphinyl or alkylsulphonyl, halogen, NO 2 , OH or di-(C 1-4  alkyl) amino; m is 2-3, n is 0-2, p is 0-2 and r is 0-5. In examples, these compounds are prepared by (1) dehydrating the analogue of I (R<SP>1</SP> = Me, R<SP>2</SP> = OH) to form I (where R<SP>1</SP>R<SP>2</SP> is CH 2 =), and hydrogenating this to give I R<SP>1</SP> = Me, R<SP>2</SP> = H); (2) reacting a Grignard reagent derived from a 3-phenyl(halo)benzofuran with CH 2 O to give the 3-phenyl(hydroxymethyl) benzofuran, and the latter with SOCl 2  to give a 3-phenyl(chloromethyl)benzofuran (II) (the bromomethyl analogues are also made in some eases, reacting this with NaCN to form the 3 - phenyl(cyanomethyl)benzofuran (possibly converting this to an alpha-methyl derivative) and hydrolysing the latter to the 3-phenyl (carboxymethyl)benzofuran; (3) reacting II with NaCH(CO 2 Et) 2  to give a 3-phenyl(dicarbethoxyethyl)benzofuran, and thence the dicarboxylic acid and (by decarboxylation) a 3 - phenyl(2 - carboxyethyl)benzofuran; (4) converting the acid (Z = OH) to the acid chloride (Z = Cl) and thus to the amide; (5) cyclizing an ester of a benzoylmethoxyphenylalkanoic acid, using polyphosphoric acid; (6) making a glyceryl ester by reacting 3-phenylbenzofuran-7-acetic acid with ClCH 2 CN (presumably giving the cyanomethyl ester) followed by 4-hydroxymethyl-2,2-dimethyl-1,3-dioxolan to give the corresponding ester which is then hydrolysed; (7) hydrolysing esters or esterifying acids; (8) interconverting the benzofurans and dihydrobenzofurans by (de)hydrogenation; (9) optical resolution, e.g. via the cinchonine salt; (10) converting a MeO substituted to HO with HI; (11) introducing a 2-Cl substituent with SO 2 Cl 2 ; (12) forming I where Z is NHOH or NHNH 2  by reacting a corresponding ethyl ester with NH 2 OH or N 2 H 4 , respectively. Starting materials otherwise prepared are a number of substituted benzoylmethoxybenzenes and the corresponding substituted 3-phenylbenzofurans obtained by cyclization. Therapeutic compositions for oral, parenteral or rectal administration comprise compounds of the above formula, which have antiinflammatory, antipyretic and analgesic activity.